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. 2012 May 1;5(3):366-75.
doi: 10.1161/CIRCHEARTFAILURE.111.963769. Epub 2012 Mar 27.

IL-33 independently induces eosinophilic pericarditis and cardiac dilation: ST2 improves cardiac function

Eric D Abston  1 , Jobert G Barin, Daniela Cihakova, Adriana Bucek, Michael J Coronado, Jessica E Brandt, Djahida Bedja, Joseph B Kim, Dimitrios Georgakopoulos, Kathleen L Gabrielson, Wayne Mitzner, DeLisa Fairweather
Affiliations

IL-33 independently induces eosinophilic pericarditis and cardiac dilation: ST2 improves cardiac function

Eric D Abston et al. Circ Heart Fail. .

Abstract

Background: IL-33 through its receptor ST2 protects the heart from myocardial infarct and hypertrophy in animal models but, paradoxically, increases autoimmune disease. In this study, we examined the effect of IL-33 or ST2 administration on autoimmune heart disease.

Methods and results: We used pressure-volume relationships and isoproterenol challenge to assess the effect of recombinant (r) IL-33 or rST2 (eg, soluble ST2) administration on the development of autoimmune coxsackievirus B3 myocarditis and dilated cardiomyopathy in male BALB/c mice. The rIL-33 treatment significantly increased acute perimyocarditis (P=0.006) and eosinophilia (P=1.3×10(-5)), impaired cardiac function (maximum ventricular power, P=0.0002), and increased ventricular dilation (end-diastolic volume, P=0.01). The rST2 treatment prevented eosinophilia and improved heart function compared with rIL-33 treatment (ejection fraction, P=0.009). Neither treatment altered viral replication. The rIL-33 treatment increased IL-4, IL-33, IL-1β, and IL-6 levels in the heart during acute myocarditis. To determine whether IL-33 altered cardiac function on its own, we administered rIL-33 to undiseased mice and found that rIL-33 induced eosinophilic pericarditis and adversely affected heart function. We used cytokine knockout mice to determine that this effect was due to IL-33-mediated signaling but not to IL-1β or IL-6.

Conclusions: We show for the first time to our knowledge that IL-33 induces eosinophilic pericarditis, whereas soluble ST2 prevents eosinophilia and improves systolic function, and that IL-33 independently adversely affects heart function through the IL-33 receptor.

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Figures

Figure 1
Figure 1
Recombinant (r)IL-33 treatment induces eosinophilic perimyocarditis at day 10 pi (A) without increasing cardiac viral replication (PBS vs. rIL-33 p=0.16; PBS vs. rST2 p=0.66) (B). Kruskal-Wallis test p=0.01, Mann-Whitney rank test a, p=0.006; b, p=0.19; c, p=0.06 (A). Data represent the mean±SEM of three separate experiments using 10 mice/group (A,B). Representative histology sections of myocarditis (C) and pericarditis (D) for PBS, rIL-33 or rST2-treated BALB/c mice at day 10 pi, magnification ×40 (C) and ×260 (D) respectively. Histology of eosinophilic myocarditis following rIL-33 treatment, eosinophil (arrow), magnification ×520 (E). Representative Facs of PBS 1% (top) vs. rIL-33 17% (bottom), x-axis Siglec F+, y-axis Ly6G+ (F). Absolute (left) and proportional (right) number of eosinophils in the heart by Facs analysis of live CD45+ cells, ***absolute number (left) p=0.001 and proportional/percent CD45+ (right) p=1.3×10−5 (G). Data representative of 2 separate experiments using 5–8 mice/group (G).
Figure 2
Figure 2
Cardiac function in rIL-33 or rST2 treated mice during myocarditis. BALB/c mice were infected with CVB3 at day 0 and rIL-33, rST2 or PBS injected every other day from day 1–9 pi and pressure-volume relationships assessed at day 0, 10 or 35 pi (A). Data show the mean ±SEM of 10–12 mice/group (A). Kruskal-Wallis test compares three treatment groups at day 10 or day 35 pi, *p<0.05 (A). Percent change in the average end systolic pressure (ESP), ejection fraction (EF) or end diastolic volume (EDV) at day 10 or 35 pi from day 0 for each treatment group (B).
Figure 3
Figure 3
rIL-33 induces β-adrenergic insensitivity during CVB3 myocarditis at day 10 pi (A) and in undiseased mice at day 10 (B). BALB/c mice received either CVB3 at day 0 and PBS, rIL-33 or rST2 every other day from day 1 to 9 pi (A) or PBS, rIL-33 or rST2 every other day from day 1 to 9 but no virus (B). *compares rIL-33 to PBS-treated mice (p<0.013). There were no significant differences in rST2 treated mice compared to PBS controls. Three groups were analyzed using generalized estimating equations and linear mixed effects models, †p<0.05. Data show the mean ±SEM of 10–12 mice/group. HR, heart rate; dP/dT Max, peak rate of pressure rise; CO, cardiac output; PMX, maximum ventricular power.
Figure 4
Figure 4
rIL-33 increases proinflammatory cytokines during acute CVB3 myocarditis at day 10 pi (A) and in undiseased mice at day 10 (B) by ELISA. BALB/c mice received either CVB3 at day 0 and PBS, rIL-33 or rST2 every other day from day 1–9 pi (A) or PBS, rIL-33 or rST2 every other day from day 1–9 but no virus (B). Kruskal-Wallis tests: IL-33 p=0.001, sera sST2 p=<0.0001, IL-4 p=0.004, TNF p=0.14, IL-1β p=0.0009, IL-6 p=0.006 (A) TNF p=0.18, IL-1β p=0.13, IL-6 p=0.004 (B). *compares PBS to rIL-33 or rST2 groups, #compares rIL-33 to rST2 by the Mann-Whitney rank test with a Bonferroni correction, * or # p<0.013, ** or ## p < 0.01, *** or ### p<0.001. Data represent the mean ±SEM of three separate experiments using 10 mice/group.
Figure 5
Figure 5
IL-33 directly reduces cardiac function in undiseased mice. Undiseased mice deficient (−/−) in the IL-1R (A), IL-6 (B) or IL-1RAcP (chain common to IL-1R and IL-33R/ST2L) (C) were treated with PBS, rIL-33 or rST2 every other day from day 1–9 and cardiac function assessed at day 10 (no virus) using pressure-volume relationships. Data represent the mean ±SEM of 10 mice/ group. *p<0.05, **p<0.01, ***p<0.001 by Mann-Whitney rank test.
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